Actively transcribed genes are more susceptible to nuclease digestion, an observation suggested to reflect an altered state of chromatin organization. It has been hypothesized that exposure or sequestration of chromatin domains is a higher order gene regulatory mechanism. In order to test whether tissue lineage is organized by mechanisms at the level or chromatin structure, three cardiac phenotype-conferring genes (atrial natriuretic factor, myosin light chain-1-ventricular and α-tropomyosin) have been assessed for DNase 1 sensitivity in nuclei prepared from tissues of the developing guinea pig. These data have been related to the level of tissue mRNA expression of these genes to ascertain whether the exposed state of genes can occur when transcription is low or undetectable. Although this phenomenon was evident in some cases, the data were not consistent with mechanisms at the level of chromatin structure directing tissue type.